Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance

Introduction Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused ‘plan of the day’ radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. Methods and analysis Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment. Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort). A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery. The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes. Ethics and dissemination This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities. Trial registration number NCT02447549; Pre-results


GENERAL COMMENTS
The authors submitted a study in which they tried to test within a randomized multi-center phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. I think this article is interesting and insightful, and particularly well written. However, the major points you should consider are the following: Major 1. Dose calculation is done on CT30 data set for adaptive tumor focused radiotherapy group, but the intestinal tract may be included in the target volume (especially PTV_Lar_60&PTV2_Lar_60). If flatus is present in the overlapping area of intestinal tract and target volume, the target dose would be calculated to be low and an unnecessarily high dose might be administered to satisfy the dose constraints. Therefore, it is considered that the intestinal gas in the target volume should be allowed to be overwritten with waterequivalent density. If it would be allowed, please add it to the protocol.
2. High quality of TURBT is needed to accomplish best treatment result. Please mention more about the role of TURBT in the protocol. The reviewer believe that maximal TURBT should be considered for the enrolled patients before radiation therapy.

Neil B. Desai University of Texas Southwestern Medical Center United States of America
Boston Scientific clinical trial funding and consulting in prostate cancer regarding rectal spacer hydrogel REVIEW RETURNED 08-Oct-2020

GENERAL COMMENTS
This is a well thought out, well-written and coordinated international cooperative protocol by experienced investigators in bladder cancer. A track record and preliminary investigation in the experimental interventions is established for this group. Ability to accrue is derived from prior high level/high impact trials. A key question is whether more contemporary techniques for adaptation can be extrapolated to many centers, but this is the focus of the study itself. The treatment questions are important and flexible to accommodate multiple sensitize regimens and fractionation schemes. One question would be whether the presentation of data from the UK that hypofractionation may indeed be a preferred approach would affect whether the investigators see need to enroll full number cohorts at both conventional and hypofractionated regimens or whether to focus on latter, should enrollment be challenged. But this need not be addressed now.

REVIEWER
Petra Kroon UMC Utrecht, the Netherlands REVIEW RETURNED 12-Oct-2020

GENERAL COMMENTS
Dear authors, RAIDER is an interesting study in which the added value of ART/DART is investigated in a multi-centre setting. Hopefully, the study recruitment is going well.

VERSION 1 -AUTHOR RESPONSE
Reviewer: 1 Reviewer Name: mccm hulshof Institution and Country: Amsterdamumc Please state any competing interests or state 'None declared': no conflicts of interest Comments to the Author The manuscript is a protocol of a running randomized phase II study in muscle invasive bladder cancer comparing whole bladder radiation (standard arm), tumor focused radiotherapy and dose escalated adaptive tumor focused radiotherapy. The study will answer a relevant question in bladder sparing treatment and might be able to improve technique and reducing toxicity in BST. The study protocol is too extended and complicated to be described when publishing the results and thus deserves publication in a separate manuscript. As a reviewer of the manuscript it is not my task to comment on the study design itself. My only comment to the authors would be to add under "strength and limitations" the large accepted heterogeneity in treatment and techniques allowed (dose fractionation, chemotherapy schedules and types of drugs, use of fiducials etc) which might bias the toxicity results.
• We thank the reviewer for recognising the importance of publishing the study protocol as a separate manuscript.
• Partially agree. The issue raised regarding the 'heterogeneity in treatment and technique' is recognised. It has been addressed and minimised within the manuscript and protocol as follows; o For dose fractionation, in order to manage the inclusion of both fractionation cohorts, the choice of schedule had to be confirmed by each participating site before trial commencement and then had to be used for all patients at that site. The study is separately powered for each fractionation cohort (essentially 2 trials in 1) and analysis will thus establish the safety of dose escalation with each fractionation regimen independently.
The fact that the two fractionation cohorts will be analysed separately for the primary endpoint is explained on p8 para 3 of the manuscript and, supplementary material, appendix 1 main protocol p14.
o The concurrent chemotherapy regimes were limited to those four regimes with supporting phase III and phase II outcome data. It was advised that each centre should also use the same regime for each participant within the trial where possible (manuscript p 10, para 3).
o In addition treatment allocation is by minimisation with a random element; balancing factors were centre, neo-adjuvant chemotherapy use and concomitant radiosensitising therapy use. This is described in the manuscript (p8, para 2) and in the supplementary material, appendix 1 main protocol (p29 under treatment allocation).
Given technique adopted is largely centre driven, we believe the criticism of treatment heterogeneity has been reduced as much as possible by the approaches adopted with the trial.
We have also specified within the strengths and limitations that this is a non-comparative trial design (p4, line 12) and in the main text (p21, para 3).
No further changes made to the text. Comments to the Author This is a protocol for a phase II multi-centre randomised controlled trial on muscle invasive bladder cancer. The protocol is well written and thought out, providing sufficient methodological detail. The only limitation is acknowledged by the authors, in that a comparative analysis of treatment regimens is not possible due to randomisation.
• We thank the reviewer for their time and favourable comments. No changes to the manuscript indicated.
Reviewer: 3 Reviewer Name: Takahiro Osawa Institution and Country: Hokkaido University Hospital, Japan Please state any competing interests or state 'None declared': None Comments to the Author The authors submitted a study in which they tried to test within a randomized multi-center phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. I think this article is interesting and insightful, and particularly well written. However, the major points you should consider are the following: • We thank the reviewer for their time and favourable comments.
Major 1. Dose calculation is done on CT30 data set for adaptive tumor focused radiotherapy group, but the intestinal tract may be included in the target volume (especially PTV_Lar_60&PTV2_Lar_60). If flatus is present in the overlapping area of intestinal tract and target volume, the target dose would be calculated to be low and an unnecessarily high dose might be administered to satisfy the dose constraints. Therefore, it is considered that the intestinal gas in the target volume should be allowed to be overwritten with water-equivalent density. If it would be allowed, please add it to the protocol.
• The reviewer raises an important point that was considered at the time of protocol development, i.e. how to accurately represent dose to the intestinal tract/bowel at the time of planning particularly for the large plan (PTV_Lar_60&PTV2_Lar_60).
Intestinal gas/bowel in the target volume at the time of planning was explicitly not chosen to be overridden because it incorrectly assumes that plan selection will be optimal; that the bladder has filled by a magnitude such that it adequately pushes bowel out of the target (justifying large plan selection) and so minimising dose to these structures.
We therefore made the decision to accept that that large plan would overestimate actual dose delivered to bowel if plan selection was correct. Underestimating delivered dose to bowel would have been a more critical oversight given dose escalation (p14 para 6).
The medium (and small) plans were accepted to be closer representatives of actual delivered dose to bowel. And is why the medium plan (and not large) had to meet the pre-specified mandatory dose constraints for dose escalation (p14 para 6).
This approach was also adopted in the preceding published phase I safety work (Hafeez S et al: Prospective Study Delivering Simultaneous Integrated High-dose Tumor Boost ( The supporting rationale for this approach is also described in the main manuscript (p14, para 6) and in supplementary material, appendix 2 radiotherapy planning and delivery guidelines (p24, section 4.4 normal tissue constraints).
No further changes made to the text.
2. High quality of TURBT is needed to accomplish best treatment result. Please mention more about the role of TURBT in the protocol. The reviewer believe that maximal TURBT should be considered for the enrolled patients before radiation therapy.
• We have already stated that 'all participants should have a transuretheral resection of the bladder tumour (TURBT)' (p10 para 1).
• The role of TURBT prior to radiotherapy is specified in the main text (p10 para 1) under the study treatment section and in supplementary material, appendix 1 main protocol (p23 section 10.1 pre-trial treatment). It is also included in Table 1 schedule of assessments.
The protocol did not mandate that the TURBT had to be visibility complete prior to radiotherapy. This is because it is accepted that inability to perform a complete TURBT does not necessarily preclude patients accessing bladder preservation with radiotherapy although we acknowledge that complete TURBT carries prognostic value.
No further changes made to the text. Comments to the Author This is a well thought out, well-written and coordinated international cooperative protocol by experienced investigators in bladder cancer. A track record and preliminary investigation in the experimental interventions is established for this group. Ability to accrue is derived from prior high level/high impact trials. A key question is whether more contemporary techniques for adaptation can be extrapolated to many centers, but this is the focus of the study itself. The treatment questions are important and flexible to accommodate multiple sensitize regimens and fractionation schemes. One question would be whether the presentation of data from the UK that hypofractionation may indeed be a preferred approach would affect whether the investigators see need to enroll full number cohorts at both conventional and hypofractionated regimens or whether to focus on latter, should enrollment be challenged. But this need not be addressed now.
• We thank the reviewer for their time, favourable and thoughtful comments. No changes to the manuscript indicated.